Author Archive | Anonymous

Predicting the antimalarial effect of artesunate-mefloquine combination therapy using a mechanistic pharmacokinetic-pharmacodynamic model

Background: Malaria is a mosquito-borne infectious disease, with the most severe form caused by the parasite Plasmodium falciparum. The first-line defence against uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), involving multiple administrations of two or more antimalarial drugs. ACTs are highly effective worldwide, however, recently decreased efficacy of the ACT artesunate-mefloquine has been reported […]

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A population PK-PD model of unbound Docetaxel in patients with liver impairment and identification of potential covariates for initial dosage adjustment

Objectives: Docetaxel is a commonly used anti-cancer drug. Due to higher incidence of severe neutropenia in patients with impaired liver function it is rarely given to these patients. A PK model including covariates on clearance (BSA, AAG, LF and ERMBT) have been developed for total and unbound docetaxel in normal and liver impaired patients [1]. […]

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Optimal design of time-to-event models with an emphasis on dropouts in disease progression studies

Objectives: Population optimal design is a tool to increase efficiency in drug development [1]. However, the population models used in drug development are becoming more and more advanced as the models incorporate additional variables like, for example, Time-To-Event (TTE), discrete type outcomes, etc. This increase in model complexity makes model-based optimal design more relevant but the […]

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Design of survival studies for red blood cells

Background: The lifespan of red blood cells (RBCs) is unknown. All current labelling methods contain significant flaws including loss of label from viable RBCs or reincorporation of the label into new RBCs after death of the originally labelled cells. Previously proposed models for the lifespan of RBCs either assume a fixed lifespan for all cells […]

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Can PBPK Models Predict Post-Mortem Redistribution?

Background:  Post-mortem redistribution (PMR) refers to changes in drug concentrations that can occur after death due to various processes such as passive diffusion from solid organs.1  Drug concentrations can also differ significantly depending on the site from which the specimen was taken.2  This can cause confusion for those trying to establish a cause of death as ‘toxic’ […]

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Population pharmacokinetics of oxypurinol in patients with gout receiving allopurinol

Background: Allopurinol, a pro-drug of oxypurinol, is the most common medicine used for prophylactic management of gout. The active metabolite of allopurinol, oxypurinol, is responsible for the urate lowering effect of allopurinol and is primarily renally excreted. Treatment response to allopurinol is variable in people with gout supporting the need for more information about factors which […]

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The population pharmacokinetics of propofol: a meta-analysis of studies available from the OpenTCI Initiative

Aim: The aim of this study was to develop a population PK model for propofol in adults that could be used to determine optimal sampling times for a prospective pharmacokinetic study. Methods: Data from 15 pharmacokinetic studies of propofol in adults were obtained from the OpenTCI Initiative [1]. A total of 7711 concentrations from 405 […]

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Does the use of Lean Body Weight (LBW) in a modified Cockcroft-Gault (C-G) equation provide a better prediction of gentamicin clearance?

Background: The Cockcroft and Gault (C-G) method of calculating creatinine clearance (CLcr) does not appear to perform well at low concentrations of serum creatinine and the extremes of body sizes. Aim:  To evaluate the performance of a modified C-G equation to predict gentamicin clearance. Methods: Demographics and gentamicin pharmacokinetic parameters were collected from 999 subjects as part of […]

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The Effect of Study Design on Pharmacokinetics in Patients with Impaired Renal Function

Backgroud: To ensure the effect of renal function on drug exposure is precisely quantified, FDA guidance1recommends that studies recruit approximately equal subject numbers with normal renal function and mild, moderate and severe renal impairment. However, in population PK analyses it is common to pool data from various studies, resulting in an over-representation of subjects with normal […]

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A nonlinear mixed effects model to characterise lamivudine absorption and distribution

Background: Lamivudine (3TC), a potent selective inhibitor of HIV reverse transcriptase, is used in combination antiretroviral therapy (ART). 3TC pharmacokinetics is characterised by highly variable absorption and is rapidly distributed to a slow equilibrating peripheral compartment. Although not considered a candidate for routine therapeutic drug monitoring, 3TC pharmacokinetics is unaltered by concomitant anti-tuberculosis treatment, a […]

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